Tau pathology is a key feature in numerous neurodegenerative disease including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, and frontotemporal dementia and parkinsonism linked to chromosome 17. The events preceding the development of neurofibrillary and other types of tau pathology including associated neurodegeneration are largely unknown. Because tissues are generally unavailable from early stage patients with tauopathies, we intend to utilize a novel mouse model that we have generated to study the progression of neurofibrillary pathology. These transgenic mice express human tau containing an FTDP-17 mutation, P301L, and develop tau neurofibrillary tangles, neuronal loss, amyotrophy, and behavioral and motor deficits. The neurofibrillary tangles in these mice recapitulate essentially all of the features of these lesions in Human tauopathies, including Alzheimer's disease, and critically are also associated with neuronal loss. In addition, the distribution of the pathology and the psychomotor deficits in the tau mice resemble some aspects of progressive supranuclear palsy, amyotrophic lateral sclerosisparkinsonism-dementia (ALS-PD) and variants of FTDP-17. In this project we will perform a series of studies to determine the molecular mechanisms that underlie pathogenesis in the tau (P301L) transgenic mice. cDNA generated from midbrain, pons and spinal cord regions from the P301 L tau mice will be subjected to microarray analysis to identify and profile genes that have altered expression levels during the onset and progression of tangle pathology. To study the effect of tau phosphorylation on tangle formation, which has been suggested as a major initiating event in the pathogenesis of tauopathies, P301L animals will be crossed with mice over expressing either GSK3beta or p25, the constitutive activator of cdk5. Both cdk5 and GSK3beta have been proposed as major tau kinases in both normal brain and in the pathogenesis of disease. Finally, to determine if oxidative stress is associated with the pathology seen in the P301L mice, we will look at markers for oxidative damage of DNA, lipid, and protein. The information from this study will provide a greater understanding of the development of neurofibrillary pathology and associated neurodegeneration in tauopathies as well as the factors that can modify the onset and progression of the pathology.